PROJECT SUMMARY Heart disease remains the leading cause of death in the United States and other developed countries. Half of these deaths occur suddenly, typically from ventricular tachyarrhythmias that arise in the setting of acute ischemia, acquired heart disease or inherited syndromes including channelopathies and cardiomyopathies. The specialized cardiac conduction system (CCS) comprises a heterogeneous network of cells that orchestrate the initiation and propagation of a wave of electrical excitation throughout the myocardium. Accumulating evidence suggests that dysfunction of the ventricular conduction system (VCS) plays a key mechanistic role triggering a broad range of life-threatening ventricular arrhythmias, however major gaps exist in our understanding of the molecular mechanisms responsible for the formation, function and dysfunction of the VCS. Our laboratory has established new tools and identified novel genes and pathways that we hypothesize are critical for VCS formation, function and dysfunction. In this application we propose a series of experiments designed to test the biological importance of these new genes and pathways.